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Modification of Multiple Sclerosis Phenotypes by African Ancestry at HLA
Bruce A. C. Cree, MD, PhD, MCR;
David E. Reich, PhD;
Omar Khan, MD;
Philip L. De Jager, MD, PhD;
Ichiro Nakashima, MD;
Toshiyuki Takahashi, MD;
Amit Bar-Or, MD;
Christine Tong, BS;
Stephen L. Hauser, MD;
Jorge R. Oksenberg, PhD
Arch Neurol. 2009;66(2):226-233. doi:10.1001/archneurol.2008.541
Background In those with multiple sclerosis (MS), African American individuals have a more severe disease course, an older age at onset, and more often have clinical manifestations restricted to the optic nerves and spinal cord (opticospinal MS) than white persons.
Objective To determine whether genetic variation influences clinical MS patterns.
Design Retrospective multicenter cohort study.
Participants Six hundred seventy-three African American and 717 white patients with MS.
Main Outcome Measures Patients with MS were genotyped for HLA-DRB1 and HLA-DQB1 alleles. The proportion of European ancestry at HLA was estimated by genotyping single-nucleotide polymorphisms with known significant frequency differences in West African and European populations. These genotypes were correlated with the opticospinal disease phenotype, disability measures, and age at onset.
Results Subjects with DRB1*15 alleles were twice as likely to have typical MS rather than opticospinal MS (P = .001). Of the subjects with opticospinal MS or a history of recurrent transverse myelitis who were seropositive for anti–aquaporin 4 antibodies (approximately 5%), none carried DRB1*15 alleles (P = .008). Independently of DRB1*15, African ancestry at HLA correlated with disability as measured by the Multiple Sclerosis Severity Score (P < .001) and risk of cane dependency (hazard ratio, 1.36; P < .001); DRB1*15 alleles were associated with a 2.1-year earlier age at onset (P < .001).
Conclusions These data indicate that the role of HLA in MS is not limited to disease susceptibility but that genes embedded in this locus also influence clinical outcomes.
Author Affiliations: Department of Neurology, University of California–San Francisco, San Francisco (Drs Cree, Hauser, and Oksenberg, and Ms Tong); Department of Genetics, Harvard Medical School, Cambridge, Massachusetts (Dr Reich); Department of Neurology, Wayne State Medical School, Detroit, Michigan (Dr Khan); Harvard Medical School/Partners Healthcare Center for Genetics & Genomics, and Center for Neurologic Diseases, Department of Neurology, Brigham & Women's Hospital, Boston (Dr De Jager); Department of Neurology, Tohoku University School of Medicine, Sendai, Japan (Drs Nakashima and Takahashi); and Montreal Neurological Institute, McGill Medical School, Montreal, Quebec, Canada (Drs Nakashima and Bar-Or).
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